Pyrazolo-quinazoline derivatives, process for their preparation and their use as kinase inhibitors

Abstract

Pyrazolo-quinazoline derivatives of formula (Ia) or (Ib) as defined in the specification, and pharmaceutically acceptable salts thereof, processes for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful, in therapy, in the treatment of diseases associated with a disregulated protein kinase activity, like cancer.

1 . A pyrazolo-quinazoline derivative of formula (Ia). 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R is substituted or unsubstituted phenyl; 
 X is —NH—; 
 R 1  is an optionally substituted straight or branched C 1 -C 6  alkyl; 
 R 2  is —NR″R′″, wherein
 R″ is hydrogen or an optionally substituted straight or branched C 1 -C 6  alkyl; 
 R′″ is hydrogen or an optionally substituted group selected from phenyl and straight or branched C 1 -C 6  alkyl; and 
 
 A is —(CH 2 ) 2 —, —CH 2 —C(CH 3 ) 2 —, or —C(CH 3 ) 2 —CH 2 —. 
 
     
     
         2 . The compound of  claim 1 , wherein R is phenyl substituted with heterocyclyl or heterocyclylalkyl. 
     
     
         3 . The compound of  claim 2 , wherein the heterocyclyl is selected from piperazinyl, morpholinyl, and imidazolyl. 
     
     
         4 . The compound of  claim 1 , wherein R is phenyl substituted with one or more groups independently selected from halogen, hydroxy, polyfluorinated alkyl, and aminocarbonyl. 
     
     
         5 . The compound of  claim 1 , wherein R 1  is straight or branched C 1 -C 6  alkyl substituted with one or more groups independently selected from halogen and hydroxy. 
     
     
         6 . The compound of  claim 1 , wherein R 1  is unsubstituted straight or branched C 1 -C 6  alkyl. 
     
     
         7 . The compound of  claim 1 , wherein R 1  is methyl. 
     
     
         8 . The compound of  claim 1 , wherein R′″ is unsubstituted straight or branched C 1 -C 6  alkyl or straight or branched C 1 -C 6  alkyl substituted with one or more groups independently selected from halogen, hydroxy, aryl, heterocyclyl, and di-(C 1 -C 6  alkyl)amino. 
     
     
         9 . The compound of  claim 8 , wherein the aryl is phenyl. 
     
     
         10 . The compound of  claim 8 , wherein the heterocyclyl is pyridyl. 
     
     
         11 . The compound of  claim 1 , wherein A is —CH 2 —C(CH 3 ) 2 —. 
     
     
         12 . A method for treating a disease selected from the group consisting of ovarian cancer, acute myeloid leukemia, prostate cancer, breast cancer, liver cancer, melanoma, colon cancer, non-small lung cancer, pancreatic cancer, and pancreatic adenocarcinoma, comprising administering to a mammal in need thereof an effective amount of a compound of  claim 1 . 
     
     
         13 . The method of  claim 12 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         14 . A method for inhibiting Aurora 2 activity, comprising administering to a mammal in need thereof an effective amount of a compound of  claim 1 . 
     
     
         15 . The method of  claim 14 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         16 . A method for inhibiting cell cycle dependent kinase activity, comprising administering to a mammal in need thereof an effective amount of a compound of  claim 1 . 
     
     
         17 . The method of  claim 16 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         18 . A process for preparing the compound of  claim 1 , or a pharmaceutically acceptable salt thereof, comprising:
 (1) when A is —(CH 2 ) 2 —:
 st.1) reacting 2-ethoxy-2-cyclohexen-1-one with diethyl oxalate, in the presence of lithium (bis-trimethylsilyl) amide [LiN(TMS) 2 ], to obtain a compound of formula (II) 
   
       
         
           
           
               
               
           
         
         
           and treating the compound of formula (II) with a hydrazine derivative of formula (III)
   R 1 —NHNH 2   (III)
 
 
           according to step st.2a) or st.2b): 
           st.2a) in the presence of a lower alcohol to obtain a mixture of compounds of formulae (IVa) and (IVb) 
         
       
       
         
           
           
               
               
           
         
         
           and isolating the compound of formula (IVa) from the mixture; 
           st.2b) in the presence of acetic acid to obtain a compound of formula (IVa); 
           st.3) reacting the compound of formula (IVa) prepared according to step st.2a) or 
           st.2b) with dimethylformamide-di-tert-butylacetate to obtain a compound of formula (Va) 
         
       
       
         
           
           
               
               
           
         
         
           and reacting the compound of formula (Va) according to step st.4: 
           with a guanidine derivative of formula (VI)
   R—NH—C(═NH)NH 2   (VI)
 
 
           so as to obtain a compound of formula (Ia′) 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 2  is ethoxy; and converting the compound of formula (Ia′) into the compound of formula (Ia); 
         
         (2) when A is —C(CH 3 ) 2 —CH 2 —:
 st.5) reacting 2-methoxy-4,4-dimethyl-2-cyclohexen-1-one with diethyl oxalate, in the presence of [LiN(TMS) 2 ], to obtain a compound of formula (VIII) 
 
       
       
         
           
           
               
               
           
         
         
           st.6) reacting the compound of formula (VIII) with a hydrazine derivative of formula (III) according to step st.2a) or st.2b) to obtain a compound of formula (IXa) 
         
       
       
         
           
           
               
               
           
         
         
           st.7) reacting the compound of formula (IXa) with ethyl formate under basic conditions, to obtain a compound of formula (Xa) 
         
       
       
         
           
           
               
               
           
         
         
           st.8) reacting the compound of formula (Xa) with a guanidine derivative of formula (VI) to obtain a compound of formula (Ia′) 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 2  is ethoxy; and converting the compound of formula (Ia′) into the compound of formula (Ia); 
         
         (3) when A is —CH 2 —C(CH 3 ) 2 —:
 st.9) reacting 2-methoxy-5,5-dimethyl-2-cyclohexen-1-one with diethyl oxalate in the presence of sodium hydride, to obtain a compound of formula (XI) 
 
       
       
         
           
           
               
               
           
         
         
           st.10) reacting the compound of formula (XI) with a hydrazine derivative of formula (III) according to previous step st.2a) or st.2b) to obtain a compound of formula (XIIa) 
         
       
       
         
           
           
               
               
           
         
         
           st.11) reacting the compound of formula (XIIa) with dimethylformamide-di-tert-butylacetale to obtain a compound of formula (XIIIa) 
         
       
       
         
           
           
               
               
           
         
         
           st.12) reacting the compound of formula (XIIIa) with a guanidine derivative of formula (VI) to obtain a compound of formula (Ia′) 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 2  is ethoxy; and converting the compound of formula (Ia′) into a compound of formula (Ia).